The regulation of T‐cell cytokine production by ICOS–B7H2 interactions at the human fetomaternal interface

Abstract

Although T cells are the most common decidual lymphocyte subset in late pregnancy, little is known about the mechanisms controlling their function. Costimulatory signaling, mediated by inducible costimulator (ICOS)-B7H2 interactions, is a known potent regulator of T-cell activation. We aimed to determine its role in fetomaternal immunity. T cells from matched peripheral blood and term decidua were assessed for ICOS, CD4/CD8, CD45RA/CD45RO and Foxp3 expression and for alterations in cytokine production upon ICOS-B7H2 ligation. We also assessed ICOS-B7H2 communication between T cells and a trophoblast cell line (JEG3). Strong ICOS expression was observed on CD4 and CD8 decidual (d)T cells, but not peripheral (p)T cells. Among dT cells, ICOS expression was higher on the predominant CD45RO + cell population compared with CD45RA + cells. Strong ICOS expression was also seen on CD4 + Foxp3 + regulatory T cells in the decidua. ICOS ligation enhanced T-cell secretion of interferongamma (IFN-c) and interleukin-10 (IL-10), but not IL-2. The impact of ICOS stimulation was more remarkable in dT cells when compared with pT cells. T cells co-cultured with JEG3 cells promoted T-cell production of IFN-c and IL-10, an effect blocked by antibody-specific masking of major histocompatibility class I or B7H2. These findings suggest that T-cell cytokine modulation by ICOS-B7H2 interactions is important in the delicate immune balance at the fetomaternal interface. The maternal endometrial lining during pregnancy is modified from the non-pregnant state and called the maternal decidua. It represents an initial contact point for genital pathogens and, therefore, has specialized innate and adaptive immune attributes. 1 This same tissue, however, must simultaneously tolerate the growing pregnancy, allowing allogenic fetally derived placental cells to reside in direct apposition with immunocompetent maternal lymphocytes. 2 CD56 bright CD16 dim natural killer (NK)-like cells (also called decidual NK cells) and CD3 + T cells comprise the two major subsets of decidual lymphocytes. 3 The number of T cells residing in the decidua throughout pregnancy is constant, although their percentage among decidual lymphocytes increases from 10-30% in the first trimester to 60-80% in the third trimester because of a significant reduction in the number of decidual (d)NK cells. 3 Although T-cell killing functions in the decidua need to be preserved throughout pregnancy to prevent expansion of localized infections, this must always be balanced by T-cell tolerance toward fetal antigens. Therefore, exquisite control of T-cell immunity and tolerance is key to successful pregnancy.Efficient T-cell activation requires both the engagement of the T-cell receptor with the major histocompatibility/antigen complex on antigen presenting cells (APCs) and the engagement of costimulatory molecules. 4 Costimulatory signaling is also delivered by ligand-receptor binding, which positively or negatively modulates the activation level of the T cell and its subsequent functional ...

Human decidual macrophages suppress IFN-γ production by T cells through costimulatory B7-H1:PD-1 signaling in early pregnancy

“…They are absent on resting naive T cells, but are rapidly induced upon antigen recognition (Freeman et al, 2000). We have previously reported that ICOS was highly expressed on the entire T cell population in human decidua (Nagamatsu et al, 2011). The present study confirmed that PD-1 was also present in the majority of decidual T cells, a finding previously reported in a detailed description of decidual PD-1 expression patterns by another group (Taglauer et al, 2008).…”

“…We have previously shown that decidual stromal cells constitutively express B7-H1 and B7-DC, and that interactions between B7-H1 and B7-DC with their ligands are likely involved in the suppression of excessive T cell activation in the decidua (Nagamatsu et al, 2009). Enhanced expression of inducible costimulator (ICOS), a receptor for B7-H2 (Nagamatsu et al, 2011) and PD-1 (Taglauer et al, 2008) has been confirmed by us and others on a majority of the T cells residing in the decidua. Taken together, these findings imply that B7 costimulatory pathways may be critical in the fine tuning of T cell activity at the feto-maternal interface.…”

“…T cells in DMCs and PBMCs were isolated using immunomagnetic negative selection (pan T cell collection kit, MACS, Miltenyi Biotec) as previously described (Nagamatsu et al, 2011). Flow cytometric analysis was conducted to check the isolation purity by staining the collected cells with anti-CD3 antibody.…”

Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory T cells – possible implications for the ICOS/ICOS-ligand axis in disease course and resolution

“…For instance, newly diagnosed type 1 diabetic children had a defect in the induction of FoxP3 and ICOS expression [20]. Furthermore, a substantial expression of ICOS on T regs and decidual T cells was recognized to be crucial for preserving the immune homeostasis at the feto-maternal interface [21]. Of note, the induction of T cell anergy and the suppressive capacity of CD4…”

Maternal CD4+ and CD8+ T Cell Tolerance Towards a Fetal Minor Histocompatibility Antigen in T Cell Receptor Transgenic Mice1

“…Additionally, the upregulation of PDCD1 on the CD4 þ T cells in OVA-bred OT-II mice suggests that this molecule may be important in inhibiting fetus-specific maternal CD4 þ T cells that may subsequently encounter CD274-expressing trophoblast cells at the maternalfetal interface and/or CD274-expressing maternal APCs. Although our previous work demonstrates a noncritical role for PDCD1/CD274 interactions in murine pregnancy [39,40]; in experiments using human cells, expression of the ICOS and PDCD1 ligands, ICOSL and CD274, respectively, by trophoblasts and macrophages at the maternal-fetal interface suggest that these receptors function in cytokine modulation during pregnancy [39,[41][42][43][44]. Alternatively, increased expression of PDCD1 may be important in converting CD4 þ T cells into Tregs as has been suggested by others [32,33].…”